The present invention relates to the use of certain fumaric acid monoalkyl ester salts either alone or in combination with a dialkyl fumarate for preparing micro-tablets for the treatment of psoriatic arthritis, neurodermatitis, psoriasis and enteritis regionalis Crohn.
EP-A-0 188 749 already describes fumaric acid derivatives and pharmaceutical compositions containing the same for the treatment of psoriasis. Likewise, pharmaceutical compositions for treating psoriasis which contain a mixture of fumaric acid and other fumaric acid derivatives are known from DE-A-25 30 372. A content of free fumaric acid is obligatory.
DE-A-26 21 214 describes drugs for treating psoriasis which contain fumaric acid monoethyl ester and mineral salts thereof as the active ingredient. The use of fumaric acid monoethyl ester salts of calcium, zinc and magnesium and of fumaric acid dimethyl ester for the treatment of psoriasis is also known from the publication xe2x80x9cHautarztxe2x80x9d (Dermatologist) 1987, pages 279 to 285.
Finally, EP-A-0 312 697 discloses pharmaceutical compositions containing one or more compounds selected from the calcium, magnesium, zinc and iron salts of fumaric acid monomethyl ester, alone or preferably in admixture with C1-5 alkyl fumarates. A preparation according to example 4 of this document contains 87.5 mg of monoethyl fumarate Ca salts, 120.0 mg of dimethyl fumarate, 5.0 mg of monoethyl fumarate Mg salt and 3.0 mg of monoethyl fumarate Zn salt, which corresponds to 164 mg of fumaric acid. The preparation is presented in the form of enteric-coated tablets and is approved for distribution in the German market under the trademark Fumaderm(copyright).
As early as phase 3 of the clinical tests and in post-marketing studies of this product, it was found that about 60% of the patients developed gastro-intestinal symptoms in the form of diarrhoea, stomach pains and bloating during the initial phase of the Fumaderm(copyright) therapy. Other side effects are so-called flushes, i.e. redness of the face, and sensations of heat.
Even though the tablets are generally tolerated relatively well, the above-mentioned symptoms keep occurring, especially at the onset of therapy. In the course of the treatment, these undesirable side effects often decrease. However, the intake of Fumaderm(copyright) causes severe gastro-intestinal complaints in some patients. These symptoms in the stomach and intestine affect patient compliance and can be so unpleasant for the patient that therapy is sometimes discontinued.
Therefore, it was the object of the present invention to provide a pharmaceutical preparation which avoids the above-mentioned side effects, especially gastro-intestinal complaints, while the same pharmaceutical ingredients are administered.
Tests carried out by the Applicant have shown that methyl hydrogen fumarate, a metabolite of dimethyl fumarate which forms the main component of the preparation Fumaderm(copyright) initially increases the endotoxin-stimulating TNF-xcex1 secretion in human mononuclear cells of the peripheral blood (peripheral blood mononuclear cells =PBMC) and in isolated monocytes. With multiple re-exposure, the endotoxin-induced increase in TNF-xcex1 secretion is reduced, i.e. adaptation takes place.
Possibly, this initial induction of TNF-xcex1 is responsible for the known side effect of the Fumaderm(copyright) preparation such as gastro-intestinal complaints or the flush symptoms. The tendency towards decrease of endotoxin-induced TNF-xcex1 secretion after repeated methyl hydrogen fumarate exposure may be an explanation for the adaptation effect, i.e. the decrease of side effects after sustained Fumaderm(copyright) therapy. Accordingly, it was the first objective of additional tests to inhibit TNF-xcex1 secretion with other drugs and thus to control the side effects of Fumaderm(copyright) administration.
Surprisingly and unexpectedly, it was found in the course of these tests that formulation of the active ingredient in the form of micro-tablets resulted in a substantial reduction of gastro-intestinal symptoms. Therefore, the object of the invention is achieved by using one or more fumaric acid monoalkyl ester salts of the general formula 
optionally in admixture with dialkyl fumarate of the formula 
wherein A is a bivalent cation from the series consisting of Ca, Mg, Zn or Fe or a monovalent cation from the series Li, Na or K, respectively, and n denotes the numeral 1 or 2 depending on the type of cation, and, optionally, commonly used pharmaceutical excipients and vehicles for preparing a pharmaceutical composition in the form of micro-tablets or micro-pellets for the treatment of psoriatic arthritis, neurodermatitis, psoriasis and enteritis regionalis Crohn.
Preferably, the size or the mean diameter, respectively, of the micro-pellets or micro-tablets is in the range of 300 to 2.000 xcexcm, especially in the range of 500 to 1.500 xcexcm and most preferably 1.000 xcexcm.
The micro-tablets or micro-pellets may be filled in capsules or sachets and administered in this form. In addition, the micro-tablets themselves or the capsules may be provided with an enteric coating which is applied by conventional processes. Capsules may be hard or soft gelatine capsules.
Preferred compositions according to the invention contain the calcium salt of the fumaric acid monomethyl ester and/or the calcium salt of the fumaric acid monoethyl ester, optionally in admixture with dimethyl fumarate. The total weight of the active ingredients is 10 to 300 mg. Preferably, the composition in the form of micro-tablets contains 10 to 290 parts by weight of the fumaric acid monoalkyl ester (calcium salt) and 290 to 10 parts by weight of dimethyl fumarate. According to another embodiment, this composition may also contain 1 to 50 parts by weight of fumaric acid monoalkyl ester zinc salt.
Another preferred embodiment in the form of micro-tablets contains 1 to 250 parts by weight of fumaric acid monoalkyl ester (calcium salt), 250 to 10 parts by weight of dimethyl fumarate, 1 to 50 parts by weight of fumaric acid monoalkyl ester (magnesium salt) and 1 to 50 parts by weight of fumaric acid monoalkyl ester (zinc salt), the total weight of the active ingredients being 30 to 300 mg.
For systemic initiation as well as for termination of the treatment in stages (decreasing dosage), a low dose is advantageous. Such a dose may, for example, consist of 30 mg of dimethyl fumarate, 20 mg of monoethyl fumarate (calcium salt) and 3 mg of monoethyl fumarate or monomethyl fumarate (zinc salts). Therapeutic doses after an initial phase may, for example, be comprised of 20 mg of dimethyl fumarate, 87 mg of monoethyl fumarate (calcium salt) and 3.0 mg of monoethyl fumarate or monomethyl fumarate (zinc salt).
For example, the fumaric acid derivatives used in the invention are obtained according to the processes described in EP 0 312 697.
Without wishing to be bound by theoretic contemplations, it is assumed that the gastro-intestinal symptoms may be caused by local stimulation of the epithelial cells of the intestine which induces TNF-xcex1 secretion. Upon administration of conventional tablets, the ingredients of these tablets are released in the intestine in a concentration which is too high, causing local irritation of the intestinal mucous membrane. As a result of this local irritation very high concentrations of TNF-xcex1 are presumably released for a short period of time which may be responsible for the gastrointestinal side effects. On the other hand, when enteric-coated micro-tablets in capsules are applied, locally low concentrations of the active ingredients on the epithelial cells of the intestine are achieved. By peristaltic movements of the stomach, the micro-tablets are gradually moved into the small intestine with enhanced distribution of the active ingredients.
In other words, enteric-coated micro-tablets in the same dose disperse in the stomach already and are fed to the intestine in portions (boluswise), where the active ingredients are released in smaller doses. As a result, local irritation of the epithelial cells of the intestine and the release of TNF-xcex1 are avoided. This is a possible explanation for the enhanced toleration of micro-tablets in the gastro-intestinal tract vis-à-vis conventional tablets. However, it was not to be expected that a mere change in galenics would lead to such a drastic reduction of side effects.
The following examples will show the production and action of the micro-tablets according to the invention.